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ID PMID Title PublicationDate abstract
16995864 Pharmacokinetics of subcutaneously administered etanercept in subjects with psoriasis. 2006 Oct AIMS: To present the results of the pharmacokinetic analysis of the concentration-time profiles of etanercept, a soluble receptor tumour necrosis factor (TNF) antagonist, in more than 1300 subjects with psoriasis. METHODS: Pharmacokinetic samples were collected in one phase-2 and two phase-3 placebo-controlled, randomized clinical trials. Study 1 evaluated a 25-mg twice weekly (BIW) etanercept dosing regimen administered by subcutaneous (s.c.) injection for 24 weeks. Study 2 evaluated 25-mg BIW and 50-mg BIW s.c. doses for 12 weeks. Study 3 evaluated 25 mg once weekly (QW), 25 mg BIW and 50 mg BIW s.c. doses for 24 weeks. RESULTS: The mean +/- SD steady-state predose serum concentrations of etanercept for the 25-mg BIW arm at 12 weeks in study 1 were 1590 +/- 885 ng ml(-1). In study 2, mean +/- SD etanercept steady-state concentrations at 12 weeks were 1900 +/- 1110 ng ml(-1) in the 25-mg BIW group and 3830 +/- 1870 ng ml(-1) in the 50-mg BIW group. The mean +/- SD steady-state predose serum concentrations of etanercept at 12 weeks in study 3 were 768 +/- 475 ng ml(-1) for the 25-mg QW regimen, 1990 +/- 1030 ng ml(-1) for the 25-mg BIW regimen and 4020 +/- 2100 ng ml(-1) for the 50-mg BIW regimen. CONCLUSIONS: Pharmacokinetic results were highly consistent across clinical trials. The concentration-time profiles displayed dose proportionality. Etanercept concentrations in subjects with psoriasis are similar to the concentrations in subjects with rheumatoid arthritis.
16880188 Infections during tumour necrosis factor-alpha blocker therapy for rheumatic diseases in d 2007 Feb OBJECTIVE: To evaluate the rate of infections in rheumatic patients treated with tumour necrosis factor (TNF)-alpha blockers in daily practice and to determine potential risk factors of infections. METHODS: Systematic retrospective study was conducted in a tertiary-referral centre of all patients receiving at least one TNF-alpha blocker, between 1997 and December 2004. Serious infections were defined as life-threatening, requiring hospitalization or sequelae. The incidence of infections during the first TNF-alpha blocker course was compared with the incidence during the period just before such therapy, in the same patients and a number needed to harm was calculated. Univariate and multivariate analysis between patients who suffered from at least one infection during treatment or not, was conducted in order to determine potential associated risk factors. RESULTS: Among the 709 patients treated with at least one TNF-alpha blocker, 57.7% had rheumatoid arthritis; a total of 275 infectious events in 245 patients (34.5%) were reported during all treatment courses. Among these infections, 47 infections in 44 patients (6.2%) fulfilled the definition of serious infections. The incidence rate of serious infections was 3.4 +/- 38.7 per 100 patient-yrs before TNF-alpha blocker therapy vs 10.5 +/- 86.9 during the first TNF-alpha blocker course (P = 0.03, number needed to harm = 14). The single risk factor picked up by multivariate analysis to explain infections was previous joint surgery [odds ratio (OR) = 2.07, 95% confidence interval (CI) = (1.43-2.98), P < 0.0001] and, if surgery was taken out of the model, the cumulative dose of steroids [OR = 1.28 (1.04-1.59), P = 0.02]. CONCLUSION: The rate of serious infections during TNF-alpha blocker treatment observed in daily practice conditions was much higher than in phase III trials evaluating TNF-alpha blockers. Serious infections are frequent in daily practice and close monitoring is required.
16581346 Significant inhibition of TRAIL-mediated fibroblast-like synovial cell apoptosis by IFN-ga 2006 Apr The pathway of interferon-gamma (IFN-gamma)-induced suppression in tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis of fibroblast-like synovial cells (FLS) was investigated. rTRAIL triggered FLS apoptosis in a type II cell death manner, whereas IFN-gamma pretreatment significantly inhibited TRAIL-mediated apoptosis. As disruption of mitochondrial transmembrane potential (DeltaPsim), Leu-Glu-His-Asp ase (IETD ase) activity, and the appearance of hypodiploid DNA + cells were markedly suppressed in IFN-gamma-treated FLS in response to TRAIL, IFN-gamma-induced suppression was supposed to achieve at upstream of caspase-8. IFN-gamma rapidly phosphorylated signal transducers and activators of transcription 1 (STAT1), STAT3, and STAT6 as well as ERK, whereas enhanced neither phosphorylation of Akt nor nuclear translocation of nuclear factor kappaB (NF-kappaB) p65. Janus kinase (JAK)-induced phosphorylation of STAT1/3/6, which acts at translational regulation, seemed to be crucial because chemical inhibition of JAK as well as cycloheximide (CHX) abolished both the phosphorylation of STAT1/3/6 and the IFN-gamma-induced inhibitory effect. Although ERK was phosphorylated through IFN-gamma, chemical inhibition of ERK by PD98059 did not abolish the IFN-gamma-induced inhibitory effect. The authors tried to determine the responsible molecules; however, expression of TRAIL receptors; pro-caspase-3/-8/-9; Fas-associated death domain protein (FADD); tumor necrosis factor receptor 1-associated death domain protein (TRADD); silencer of death domain (SODD); FLICE inhibitory protein (FLIP); and Bcl-2, Bcl-xL, and Bax in FLS was not modulated by IFN-gamma. Although the authors have not yet clarified the precise mechanism, these data suggest that IFN-gamma/JAK/STAT pathway, which is supposed to be activated in inflammatory rheumatoid arthritis (RA) synovial tissues, contributes to form apoptosis resistance phenotype of the cells in situ, leading to a marked increase in cellularity of synovial cells.
16563716 Different ratios of eicosapentaenoic and docosahexaenoic omega-3 fatty acids in commercial 2007 Jan The use of fish oil (FO) as a dietary supplement to prevent or reduce the severity of cardiovascular diseases and autoimmune disorders such as rheumatoid arthritis is receiving much attention. Several recent reports indicate that eating fish often or the use of small doses of FO capsules appears to have benefits against cardiovascular diseases. We have reported in the past that diets enriched with FO protect against renal diseases and prolong the life span of autoimmune-prone mice compared to corn oil (CO) diets. However, the optimum ratio of eicosapentaenoic acid (EPA) to docosahexaenoic acid (DHA) in commercially available FOs to reduce the production of various pro-inflammatory cytokines has not been well established. We, therefore, obtained deodorized FO from three sources containing different EPA/DHA contents, fed them to C57BL/6 mice for 8 weeks in a 10% (vol/wt) diet (oil A, 11/10; oil B, 14/9; oil C, 23/14) and compared them with (10%) CO-fed mice as control. TNF-alpha, IL-6 and IL-1beta were measured by enzyme-linked immunosorbent assay in thioglycollate-induced macrophages, 8 and 24 h after lipopolysaccharide treatment. The results showed a significant decrease in TNF-alpha after only 8 h in oil C. After 24 h, TNF-alpha, IL-6 and IL-1beta levels decreased only in mice fed oil C, although nonsignificant decreases were seen in mice fed oil A compared to mice fed CO. The antioxidant enzymes, catalase and glutathione transferase, were higher in kidneys of mice fed oil C compared to mice fed CO. The study suggests that anti-inflammatory activity may vary among different sources of FO due to variations in EPA/DHA content.
18758357 IL-20 may contribute to the pathogenesis of human intervertebral disc herniation. 2008 Sep 1 STUDY DESIGN: The gene expression of interleukin (IL)-20 on human herniated intervertebral disc. OBJECTIVE.: To elucidate the role of novel cytokine IL-20 in the pathogenesis of human intervertebral disc (IVD) herniation. SUMMARY OF BACKGROUND DATA: IL-20 is involved in inflammatory diseases such as psoriasis, atherosclerosis, and rheumatoid arthritis, etc. However, IL-20 is never reported to be associated with the pathogenesis of human disc herniation. METHODS: Twenty consecutive patients who were diagnosed with IVD herniation and received open discectomy were included in this study. The retrieved disc material specimens and the isolated primarily cultured disc cells were immunohistochemically stained to detect the expression of IL-20 and its receptor subunits (IL-20R1, IL-20R2, and IL-22R1). Besides, to investigate the in vitro response of IL-20 on human herniated intervertebral disc, we analyzed the effects of IL-20 alone, in combination with IL-1beta, and IL-1beta alone on the gene expression and protein levels of various cytokines, chemokines, matrix metalloproteinases (MMPs), etc. RESULTS: IL-20 and its receptors were detectable in human herniated disc tissues and isolated disc cells. In vitro, IL-1beta induced the expression of IL-20. Furthermore, IL-20 induced transcripts of IL-1beta, IL-6, vascular endothelial growth factor (VEGF), MMP-3, and monocyte chemoattractant protein (MCP-1) on primarily cultured human disc cells. IL-1beta induced transcripts of IL-1beta, IL-6, IL-8, VEGF, MMP3, and MCP-1. IL-20 combined with IL-1beta induced transcripts of tumor necrosis factor-alpha (TNF-alpha), IL-1beta, IL-6, IL-8, MMP-3, and MCP-1 to a level higher than those found in cells treated with IL-20 or IL-1beta alone.Enzyme-linked immunosorbent assay, analysis also showed that IL-20 combined with IL-1beta up-regulated the secretion of TNF-alpha, IL-6, IL-8, and MCP-1. CONCLUSION: IL-20 induces proinflammatory, chemotaxtic, and matrix degradative responses in IVD cells especially in combination with IL-1beta. Our study suggests that IL-20 plays an important role in the pathogenesis of disc herniation.
18186919 Perispinal etanercept: potential as an Alzheimer therapeutic. 2008 Jan 10 Tumor necrosis factor-alpha (TNF) is one of a number of systemic and immunomodulating cytokines that generally act to promote acute-phase reactions but can drive degenerative changes when chronically elevated. Traditional focus on TNF has been directed at these inflammation-related functions. Of particular relevance to intersections between neuroinflammation and neurodegeneration is the ability of TNF to increase expression of interleukin-1 (IL-1), which in turn increases production of the precursors necessary for formation of amyloid plaques, neurofibrillary tangles, and Lewy bodies. More recent data have revealed that TNF, one of the few gliotransmitters, has strikingly acute effects on synaptic physiology. These complex influences on neural health suggest that manipulation of this cytokine might have important impacts on diseases characterized by glial activation, cytokine-mediated neuroinflammation, and synaptic dysfunction. Toward such manipulation in Alzheimer's disease, a six-month study was conducted with 15 probable-Alzheimer patients who were treated weekly with perispinal injection of Etanercept, an FDA-approved TNF inhibitor that is now widely used for treatment of rheumatoid arthritis and other systemic diseases associated with inflammation. The results demonstrated that perispinal administration of etanercept could provide sustained improvement in cognitive function for Alzheimer patients. Additionally, the authors were impressed by the striking rapidity with which these improvements occurred in the study patients. An example of this rapid improvement is presented in this issue as a case report by Tobinick and Gross. Such rapid gain of function inspires speculation about the role of gliotransmission or other equally rapid synaptic events in the relationship of TNF to Alzheimer-impacted neurophysiology. Because of the inability of large molecules such as etanercept to cross the blood brain barrier following conventional systemic administration, it is likely that the more direct drug delivery system pioneered by Tobinick also contributed to the effectiveness of the treatment. If so, this system could be useful in drug delivery to the brain in other neural disorders, as well as in animal research studies, many of which currently employ delivery strategies that inflict damage to neural cells and thus engender neuroinflammatory responses.
17990769 [Accuracy improvement of acetabular component placement using non-image based surgical nav 2007 Oct OBJECTIVE: To improve the accuracy of the acetabular component placement using the non-image based surgical navigation system. METHODS: Twenty-three patients (14 males, 9 females; age, 28-55 years; 26 hips) with hip disease underwent the total hip arthroplasty (THA) using the non-image based surgical navigation system from February 2004 to April 2006. Rheumatoid arthritis was found in 3 patients (3 hips), necrosis of the femoral head in 6 patients (6 hips), and osteoarthritis in 14 patients (16 hips). All the patients were randomly divided into the following 2 groups: the navigated group (11 patients, 13 hips), treated by THA using the non-image based surgical navigation system; and the control group (12 patients, 13 hips), treated by the traditional THA. According to the design of the study, the acetabular component was placed in the best inclination angle (45 degrees) and the anteversion angle (15 degrees). The postoperative component position was examined. RESULTS: No fracture, dislocation, infection or injury to the sciatic nerve was found. In the navigated group, the inclination and the anteversion reached 15.4 +/- 1.4 degrees and 45.5 +/- 1.3 degrees, respectively. In the control group, the inclination and the anteversion were 13.9 +/- 7.6 degrees and 43.7 +/- 6.4 degrees, respectively. The inclination difference was considered statistically significant (P < 0.01). All the patients were followed up for 10-40 months,averaged 26 months. In the navigated group, the postoperative average Harris hip score was 95 (range, 85-110), with an excellent result in 11 hips and a good result in 2 hips. In the control group, the postoperative average Harris hip score was 92 (range, 75-110), with an excellent result in 9 hips, a good result in 3 hips, and a fair result in 1 hip. The Harris hip score difference was considered statistically significant (P < 0.05). There was a significantly better result obtained in the navigated group than in the control group. CONCLUSION: The acetabular component can be implanted accurately by the non-image based surgical navigation system, which can reduce the incidence of the loosening of the prostheses and has an important value in clinical practice.
17913975 Pivotal advance: inhibition of HMGB1 nuclear translocation as a mechanism for the anti-rhe 2008 Jan Gold compounds such as gold sodium thiomalate (GST) can reduce the symptoms of rheumatoid arthritis (RA), although their mechanism of action is not well defined. As the proinflammatory mediator high mobility group box chromosomal protein 1 (HMGB1) may play a role in the pathogenesis of RA, we have performed in vitro studies to investigate whether GST inhibits HMGB1 release as the basis of its mode of action. Murine RAW 264.7 or human THP-1 macrophage cells were stimulated in culture with agents causing extracellular HMGB1 release, including LPS, IFN-gamma, polyinosinic:polycytidylic acid, IFN-beta, or NO in the presence of GST, ranging from 0 microM to 250 microM. Secretion and intracellular location of HMGB1 were assessed by Western blotting, HMGB1-specific ELISPOT assay, and immunofluorescent staining. In parallel, TNF and IFN-beta levels were analyzed by ELISPOT and/or ELISA. Supernatant NO production was analyzed by the Griess method. At pharmacologically relevant doses, GST inhibited the extracellular release of HMGB1 from activated macrophages and caused the nuclear retention of this protein; in contrast, no effects were observed on the secretion or production of TNF. Release of the key endogenous mediators of HMGB1 translocation, IFN-beta and NO, was inhibited by GST. This inhibition required gold, as sodium thiomalate did not affect the responses measured. Furthermore, gold chloride also inhibited release of HMGB1. Together, these results suggest a new mechanism for the anti-rheumatic effects of gold salts in RA and the potential of drugs, which interfere with intracellular HMGB1 transport mechanisms, as novel agents to treat RA.
17599356 Crystal structures of MMP-9 complexes with five inhibitors: contribution of the flexible A 2007 Aug 24 Human matrix metalloproteinase 9 (MMP-9), also called gelatinase B, is particularly involved in inflammatory processes, bone remodelling and wound healing, but is also implicated in pathological processes such as rheumatoid arthritis, atherosclerosis, tumour growth, and metastasis. We have prepared the inactive E402Q mutant of the truncated catalytic domain of human MMP-9 and co-crystallized it with active site-directed synthetic inhibitors of different binding types. Here, we present the X-ray structures of five MMP-9 complexes with gelatinase-specific, tight binding inhibitors: a phosphinic acid (AM-409), a pyrimidine-2,4,6-trione (RO-206-0222), two carboxylate (An-1 and MJ-24), and a trifluoromethyl hydroxamic acid inhibitor (MS-560). These compounds bind by making a compromise between optimal coordination of the catalytic zinc, favourable hydrogen bond formation in the active-site cleft, and accommodation of their large hydrophobic P1' groups in the slightly flexible S1' cavity, which exhibits distinct rotational conformations of the Pro421 carbonyl group in each complex. In all these structures, the side-chain of Arg424 located at the bottom of the S1' cavity is not defined in the electron density beyond C(gamma), indicating its mobility. However, we suggest that the mobile Arg424 side-chain partially blocks the S1' cavity, which might explain the weaker binding of most inhibitors with a long P1' side-chain for MMP-9 compared with the closely related MMP-2 (gelatinase A), which exhibits a short threonine side-chain at the equivalent position. These novel structural details should facilitate the design of more selective MMP-9 inhibitors.
17295915 The PedsQL as a patient-reported outcome in children and adolescents with fibromyalgia: an 2007 Feb 12 BACKGROUND: Fibromyalgia is a chronic health condition characterized by widespread musculoskeletal pain, multiple tender points on physical examination, generalized muscular aching, stiffness, fatigue, nonrestorative sleep pattern, cognitive dysfunction, and mood disturbance. Recently, the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) Fibromyalgia Syndrome Workshop ranked and prioritized the domains that should be consistently measured in fibromyalgia clinical trials, specifically, pain, generic health-related quality of life, fatigue, sleep quality, and physical function. The focus of these deliberations was exclusively on adult patients, and to our knowledge, these domains have not been previously tested within a multidimensional framework in children and adolescents with fibromyalgia. METHODS: An analysis to determine the feasibility, reliability, and validity of the PedsQL 4.0 (Pediatric Quality of Life Inventory) Generic Core Scales, PedsQL Multidimensional Fatigue Scale, and PedsQL Rheumatology Module Pain and Hurt Scale as patient-reported outcome (PRO) measures for pediatric patients with fibromyalgia. The PedsQL Scales were completed by 59 families in a pediatric rheumatology clinic in a large children's hospital. RESULTS: The PedsQL evidenced minimal missing responses (0.53% patient self-report, 0.70% parent proxy-report), achieved excellent reliability for the Generic Core Scales Total Scale Score (alpha = 0.88 patient self-report, 0.87 parent proxy-report), the Multidimensional Fatigue Scale Total Scale Score (alpha = 0.94 patient self-report, 0.94 parent proxy-report), and acceptable reliability for the 4-item Rheumatology Module Pain and Hurt Scale (alpha = 0.68 patient self-report, 0.75 parent proxy-report). The PedsQL Generic Core Scales and Multidimensional Fatigue Scale significantly distinguished between pediatric patients with fibromyalgia and healthy children. Pediatric patients with fibromyalgia self-reported severely impaired physical and psychosocial functioning, significantly lower on most dimensions when compared to pediatric cancer patients receiving cancer treatment, and significantly lower on all dimensions than pediatric patients with other rheumatologic diseases. Patients with fibromyalgia self-reported significantly greater pain and fatigue than pediatric patients with other rheumatologic conditions, and generally more fatigue than pediatric patients receiving treatment for cancer. CONCLUSION: The results demonstrate the excellent measurement properties of the PedsQL Scales in fibromyalgia. These PedsQL Scales measure constructs consistent with the recommended OMERACT Fibromyalgia Syndrome Workshop domains. The findings highlight the severely impaired HRQOL of pediatric patients with fibromyalgia. Regular monitoring of pediatric patients with fibromyalgia will help identify children and adolescents at risk for severely impaired HRQOL. These PedsQL Scales are appropriate outcome measures for clinical trials and health services research for pediatric patients with fibromyalgia.
16702443 Discovery and characterization of triaminotriazine aniline amides as highly selective p38 2006 Aug The p38 mitogen-activated protein (MAP) kinases are a family of serine/threonine protein kinases that play important roles in cellular responses to inflammation and external stress. Inhibitors of the p38 MAP kinase have shown promise for potential treatment of inflammatory disorders such as rheumatoid arthritis, acute coronary syndrome, psoriasis, and Crohn's disease. We identified a novel class of p38 inhibitors via high-throughput screening. PS200981 [3-(4-(1,4-diazepan-1-yl)-6-(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methylamino)-1,3,5-triazin-2-ylamino)-4-methylbenzamide], a representative compound identified from screening a collection of combinatorial libraries, amounting to 2.1 million compounds, inhibits p38alpha kinase and the lipopolysaccharide (LPS)-induced increase in tumor necrosis factor (TNF) alpha levels in cell media of human monocytes with IC50 values of 1 microM. The screening data revealed a preferred synthon, 3-amino-4-methyl benzamide, which is critical for the activity against p38. This synthon appeared almost exclusively in screening hits including PS200981, and slight variations of this synthon including 3-amino benzamide and 2-amino-4-methyl benzamide also contained in the library were inactive. PS200981 is equally potent against the alpha and beta forms of p38 but did not inhibit p38 gamma and is >25-fold selective versus a panel of other kinases. PS200981 inhibited the LPS-induced increase in TNFalpha levels when administered at 30 mg/kg to mice. Selectivity and in vivo activity of this class of p38 inhibitors was further demonstrated by PS166276 [(R)-3-(4-(isobutyl(methyl)-amino)-6-(pyrrolidin-3-ylamino)-1,3,5-triazin-2-ylamino)-4-methylbenzamide], a highly structurally related but more potent and less cytotoxic inhibitor, in several intracellular signaling assays, and in LPS-challenged mice. Overall, this novel class of p38 inhibitors is potent, active in vitro and in vivo, and is highly selective.
16580896 Tumor necrosis factor-alpha: alternative role as an inhibitor of osteoclast formation in v 2006 Aug TNFalpha is known to stimulate the development and activity of osteoclasts and of bone resorption. The cytokine was found to mediate bone loss in conjunction with inflammatory diseases such as rheumatoid arthritis or chronic aseptic inflammation induced by wear particles from implants and was suggested to be a prerequisite for the loss of bone mass under estrogen deficiency. In the present study, the regulation of osteoclastogenesis by TNFalpha was investigated in co-cultures of osteoblasts and bone marrow or spleen cells and in cultures of bone marrow and spleen cells grown with CSF-1 and RANKL. Low concentrations of TNFalpha (1 ng/ml) caused a >90% decrease in the number of osteoclasts in co-cultures, but did not affect the development of osteoclasts from bone marrow cells. In cultures with p55TNFR(-/-) osteoblasts and wt BMC, the inhibitory effect was abrogated and TNFalpha induced an increase in the number of osteoclasts in a dose-dependent manner. Osteoblasts were found to release the inhibitory factor(s) into the culture supernatant after simultaneous treatment with 1,25(OH)(2)D(3) and TNFalpha, this activity, but not its release, being resistant to treatment with anti-TNFalpha antibodies. Dexamethasone blocked the secretion of the TNFalpha-dependent inhibitor by osteoblasts, while stimulating the development of osteoclasts. The data suggest that the effects of TNFalpha on the differentiation of osteoclast lineage cells and on bone metabolism may be more complex than hitherto assumed and that these effects may play a role in vivo during therapies for inflammatory diseases.
16574519 High prevalence of asymptomatic vertebral fractures in post-menopausal women receiving chr 2006 Aug Glucocorticoid (GC)-induced osteoporosis mostly affects trabecular bone of vertebrae. Only 30% of vertebral fractures are symptomatic, yet both clinical and radiological vertebral fractures have been associated with increased mortality and morbidity. The aims of this cross-sectional, outpatient-based study were to measure the prevalence of asymptomatic vertebral fractures in a large sample of post-menopausal women given GCs for different diseases; to compare prevalence of asymptomatic vertebral fractures according to disease, GC treatment and major risk factors; and to assess the quality of life in GC users with and without asymptomatic vertebral fractures. 551 patients referring to 39 centers as outpatients for their programmed follow-up and satisfying the inclusion criteria were included in the analysis. Each patient underwent structured medical interview (including dose and duration of GC therapy, major risk factors for osteoporosis, the quality of life questionnaire of the European Foundation for Osteoporosis (QUALEFFO) and a back function score questionnaire), thoraco-lumbar radiographs and subsequent morphometry; for 253 and 437 patients, respectively, lumbar spine bone mineral density (BMD) assessed by dual energy X-ray absorptiometry and calcaneal bone stiffness assessed by quantitative ultrasonometry were available. The prevalence of asymptomatic vertebral fractures resulted >37%, with >14% of patients having two or more asymptomatic vertebral fractures and was much higher than that found in epidemiological studies on healthy women. Distribution of asymptomatic vertebral fractures along the spine showed a bimodal pattern, with two peaks at T7 and T11. The prevalence of asymptomatic vertebral fractures clearly increased with age. Differences in prevalence among diseases were evidenced. When controlled for age, GC cumulative dose, duration of therapy and personal history of fractures, the adjusted prevalences were 30.77% for systemic lupus erythematosus, 33.78% for rheumatoid arthritis, 37.78% for asthma/chronic obstructive pulmonary disease, 43.20% for polymyalgia rheumatica and 43.36% for diseases grouped as "other vasculitides/connective tissue diseases". No significant association was found with GC cumulative dose and duration of therapy. Established risk factors for osteoporosis (except for age, years since menopause and personal history of fractures), lumbar spine BMD, calcaneal stiffness and QUALEFFO score were not associated with number and severity of asymptomatic vertebral fractures. Underlying disease is likely to contribute to the risk of fracture, but disease by itself could not be dissected from GC regimen. Vertebral fractures should be looked for carefully in all post-menopausal women receiving long-term systemic GCs since they can be asymptomatic and are scarcely predictable.
16525725 p38MAPK mediates IL-1-induced down-regulation of aggrecan gene expression in human chondro 2006 Apr The pleiotropic cytokine interleukin 1 (IL-1) is considered to be the principal inducer of mediators of cartilage degradation in both, osteoarthritis (OA) and rheumatoid arthritis (RA). IL-1 activates numerous signaling pathways involved in cartilage destruction and dedifferentiation of chondrocytes. In this study, we analyzed expression and functional effects of IL-1 in human chondrocytes. We found an IL-1-induced reduction in the expression of the cartilage specific proteoglycan aggrecan as an indicator for the IL-1-mediated dedifferentiation of chondrocytes. To block the IL-1-induced signaling pathways specifically, we incubated human chondrocytes and cartilage explants with IL-1 in the presence of different signal transduction inhibitors and analyzed their effect on aggrecan mRNA expression and IL-6 secretion. IL-6 has been found to act synergistically in the IL-1-induced suppression of the proteoglycan synthesis in chondrocytes. Our results led to the identification of p38MAPK and/or PI3K/JNK as being crucial for IL-1-induced IL-6 secretion by chondrocytes. IL-1-induced down-regulation of aggrecan expression was found to be mediated by p38MAPK and/or ERK1/2. The identification and characterization of these signaling pathways will enable us to develop new modulation strategies for therapeutic use in inflammatory joint diseases.
16112121 Statins inhibit hypoxia-induced endothelial proliferation by preventing calcium-induced RO 2006 Apr Pathological hypoxia plays an important role in many diseases, such as atherosclerosis, cancer, and rheumatoid arthritis. The aim of the present study was to examine the effects of different statins on hypoxia-induced endothelial cell signalling. Human umbilical cord vein endothelial cells (HUVEC) were treated with NaCN (CN, 2.5 mmol/l) to simulate a transient hypoxia. The CN-induced increase of endothelial cell numbers was significantly (n = 10, p < 0.01) reduced by the Ca(2+) chelator BAPTA (10 micromol/l), or the reactive oxygen species (ROS) scavenger N-acetylcysteine (ACC, 1 mmol/l), or the NAD(P)H-oxidase inhibitor diphenyleneiodonium (DPI, 5 micromol/l). In detail, cell numbers were (in percentage of control): 163.24 (CN), 90.06 (CN+ACC), 92.06 (CN+DPI). Intracellular-Ca(2+) and -ROS, analysed by fluorescence imaging, were significantly increased by CN. Interestingly, the CN-induced increase of ROS was in part Ca(2+)-dependent, whereas the Ca(2+) increase was not ROS-dependent. Simvastatin (5 micromol/l), fluvastatin (2.5 micromol/l), and cerivastatin (0.1 micromol/l) all reduced CN-induced proliferation, ROS generation and Ca(2+) increase. Cell viability was not reduced by the statins and the antiproliferative effect was completely reversed by mevalonate (500 micromol/l). In conclusion our study demonstrates that statins block hypoxia-associated endothelial proliferation by preventing the increase of Ca(2+) and ROS.
18480386 Adenocarcinoid tumor of the extrahepatic biliary tract. 2008 Oct The term adenocarcinoid was first coined by Warkel et al in 1978 to describe a group of uncommon low-grade malignant appendiceal tumors with morphologic and histochemical evidence of both glandular (adenocarcinoma) and neuroendocrine (carcinoid) differentiation for which several terms have been used in the past. Although the appendix is the most frequent site of this tumor, similar neoplasms have been reported also in other sites, such as colon, gallbladder, Vater's ampulla, and stomach. The biologic and clinical behavior of adenocarcinoid is still unclear. Provided that it can metastasize, a recent meta-analysis on appendiceal adenocarcinoids showed that right hemicolectomy is not required when the tumor is completely excised and there is no cecal involvement. In this article, the clinicopathologic features of an adenocarcinoid tumor occurring in the extrahepatic biliary tract with infiltration of the common hepatic duct wall that, to the best of our knowledge, represents the first report in this site is described.
18477219 Glomeruloid hemangioma. 2008 Jun A 64-year-old Japanese woman suffering from idiopathic thrombocytopenic purpura was treated with prednisolone. During the course of steroid withdrawal she developed parotid gland enlargement and cervical lymph node swelling with multiple dome-shaped red papules on her trunk and upper limbs. On admission the patient was found to have numbness of her lower limbs (polyneuropathy), lymph node swelling (organomegaly), high glucose level (endocrinopathy), Bence-Jones protein-kappa in the urine (M protein) and skin with hyperpigmentation, hypertrichosis and multiple glomeruloid hemangiomas (skin abnormalities), indicating polyneuropathy-organomegaly-endocrinopathy-M-protein-skin abnormality (POEMS) syndrome. The patient was also found to have peripheral edema, ascites, and pleural effusion. The glomeruloid hemangiomas had intravascular capillary growth, which was composed of conglomerates of capillaries resulting in structures resembling renal glomeruli. Cells within the capillary loops were lined by endothelial cells with scant cytoplasm (CD31(+)/CD34(+)/CD68(-)/CD105(+)/UEA-1(+)) while the outer surfaces of the loops were covered by either swollen endothelial cells containing PAS- and immunoglobulin-positive eosinophilic hyaline globules (CD31(+)/CD34(-)/CD68(-/+)/CD105(-)/UEA-1(-)) or cells without globules. These two phenotypically different endothelial cells were separated by alpha-smooth muscle actin-positive pericytes. Pericytes and endothelial cells covering the outer surface of the loops were bordered by basement membrane. Biopsy of parotid gland and lymph node indicated Sjögren's syndrome and Castleman's disease of a hyaline-vascular type, respectively. Resumed prednisolone therapy has been successful, and the patient was left with minimal residual symptoms. Glomeruloid hemangioma is a specific marker of POEMS syndrome and is related to Castleman's disease. Idiopathic thrombocytopenic purpura and Sjögren's syndrome may also be related.
17937678 Clonality analysis of lymphoproliferative disorders in patients with Sjögren's syndrome. 2007 Nov The aim of this study was to clarify the nature of the clonal lymphocyte infiltration in Sjögren's syndrome (SS) patients associated with lymphoproliferative disorders. We examined B cell clonality in lymphoproliferative tissues from six primary SS patients associated with lymphoproliferative disorders or lymphoma by cloning and sequencing of the gene rearrangement of the immunoglobulin heavy chain complementarity determining region 3 (IgVH-CDR3). Three patients with sequential observation showed progressional clonal expansion with the presence of the same subclone in different tissues during the course of disease. Among them, one patient developed mucosa-associated lymphoid tissue (MALT) lymphoma in glandular parotid. The other three SS patients concomitant with malignant B cells lymphomas showed different clonal expansion of B cells between nodal sites and salivary glands. The cloanality analysis indicated that monoclonal B cell population could spread from one glandular site to another site during the course of SS, suggesting that the malignant clone may arise from the general abnormal microenvironment, not restricted to the glandular tissue, in some SS patients.
16819265 [A case in which the subject was affected by Listeia meningoencephalitis during administra 2006 Jun The subject was a 22-year-old woman who developed high fever and arthralgias and eruptions in the extremities around June 2005. She sought medical advice at a nearby dermatology clinic, where hepatic dysfunction was noted on blood testing. The patient was thus hospitalized the next day. Although CRP levels were significantly high, no sign of infection was observed and bone marrow cell differentiation was normal. Adult onset Still's disease was diagnosed based on the observation of persistent high fever >39 degrees C, eruptions, increased leukocytes, pharyngeal pain, splenomegaly, hepatic dysfunction, negative autoantibody results from blood testing, and high serum ferritin levels. Administration of prednisolone 30 mg/day was initiated, but proved ineffective. Steroid pulse therapy was conducted, and the subject was transferred to our medical facility for continued treatment. Attempts were made to control the disease using combined steroid and cyclosporine administration; but exacerbation of high serum ferritin levels and hepatic dysfunctions were observed, so a second course of steroid pulse therapy was conducted. Symptoms improved temporarily, but steroid levels were difficult to reduce. Cyclosporine was therefore replaced by methotrexate, and administration of infliximab was initiated. In the course of treatment, administration of a sulfamethoxazole/trimethoprim combination was initiated, but was discontinued due to suspicion of drug-induced hepatic injury. A second administration of infliximab was conducted in late August, and rapid improvements in clinical symptoms and abnormal test values was observed. However, high fever and headache developed suddenly in early September. Based on the results of spinal fluid testing, blood and spinal fluid cultures and MRI of the head, Listeria meningoencephalitis was diagnosed. Diplopia and impaired consciousness occurred during the disease course, and formation of a brain abscess was observed on imaging. However, symptoms were controlled by long-term combination administration of ampicillin and gentamicin. Administration of infliximab was discontinued for treatment of adult onset Still's disease, and steroid levels were reduced following double-membrane filtration plasma exchange. On follow-up, no relapse of symptoms or abnormalities in blood test values were observed, so the subject was discharged from our medical facility in December 2005. In treatment for rheumatic diseases, a dramatic improvement in treatment results for pathologies displaying tolerance against conventional treatments has been acquired with the development of biological drugs. However, opportunistic infections represent a serious problem, and appropriate preventative measures are required. The present report describes a case in which the subject was affected by Listeria meningoencephalitis during administration of infliximab for steroid-dependent adult Still's disease. Since listeriosis is one of the complications, along with tuberculosis, that warrants precautionary measures, this case is reported and discussed.
17009014 Activation of MKK4 (SEK1), JNK, and c-Jun in labial salivary infiltrating T cells in patie 2007 Feb We wanted to determine via immunohistochemistry, whether or not c-Jun NH2-terminal kinase (JNK) cascade is activated in labial salivary infiltrating T cells in patients with Sjögren's syndrome (SS). Six patients with primary SS were selected for this study. Phosphorylation of mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) (SEK1), JNK, and c-Jun in salivary infiltrating T cells was studied using immunohistochemistry assay, including mirror section technique. Phosphorylated forms of MKK4, JNK, and c-Jun were detected in salivary infiltrating mononuclear cells. Expression of phosphorylated JNK was found in both CD4+ T cells and CD8+ T cells. Moreover, co-expression of phosphorylated JNK and c-Jun was demonstrated in the mirror sections. The results of this study suggest that the JNK cascade is activated in salivary infiltrating CD4+ T cells and CD8+ T cells in SS patients, which appears to contribute to the inflammatory salivary microenvironment of SS.